Summary Iron (Fe) is an essential element that serves as a biochemical co-factor for a wide variety of enzymes and proteins that function in oxygen transport, mitochondrial oxidative phosphorylation, DNA replication and repair, intermediary metabolism, lipid metabolism, chromatin modification and a host of other critical physiological processes. Fe deficiency is the most common nutritional deficiency on earth, with health consequences that include anemia, delayed growth and development, abnormal motor and cognitive function, decreased immune function, thermoreguatory defects, fatigue and decreased work performance. While Fe deficiency leads to severe health consequences, the detailed molecular mechanisms that allow graded responses to a range of severity of Fe deficiency are not well understood. This proposal describes avenues of investigation to understand fundamental mechanisms whereby eukaryotic cells respond and adapt to Fe deficiency. The first specific aim outlines experiments to decipher the mechanisms by which the yeast Cth1 and Cth2 proteins differentially target mRNAs for degradation in response to Fe deficiency, leading to cellular metabolic adaptation to allow cells to cope with reduced Fe availability. The second specific aim describes experiments to understand how expression of the Cth1 and Cth2 proteins is exquisitely fine-tuned in response to Fe deficiency, the physiological importance of this regulation with respect to Fe homeostasis and its potential link to changes in cell cycle progression. Given the common occurrence of Fe deficiency and its disproportionate affects on the health of women and children, the studies outlined in this application will provide fundamentally important information on the mechanisms by which cells homeostatically respond to Fe deficiency. PUBLIC HEALTH RELEVANCE: Fe deficiency is the most common nutritional deficiency on earth, with health consequences that include anemia, delayed growth and development, abnormal motor and cognitive function, decreased immune function, thermoregulatory defects, fatigue and decreased work performance. Given the common occurrence of Fe deficiency and its disproportionate affects on the health of women and children, the studies outlined in this application will provide fundamentally important information on the mechanisms by which cells adapt to Fe deficiency.